ABSTRACT Clearly exercise has beneficial effects on many systems in the body such as neural, metabolic and musculoskeletal systems, but it is not clear if these benefits delay the effects of aging or if aging blunts the effects of exercise. Sarcopenia and osteoporosis are major hallmarks of the aging musculoskeletal system resulting in frailty, falls, fracture, and morbidity. We have shown that muscle and bone communicate systemically through soluble factors and specifically that muscle secretes low molecular weight factors during contraction that affect bone. These factors protect osteocytes against cell death induced by either glucocorticoids or by reactive oxygen species. One of these low molecular weight factors is ?-aminoisobutyric acid, BAIBA. This molecule has previously been shown to induce the browning of white fat and improve insulin resistance. We found that BAIBA was equal or more potent than n-acetyl cysteine and estrogen to prevent osteocyte cell death. We have begun to examine the cellular mechanisms responsible for the protective effects of BAIBA against H2O2 and found that mitochondria are dynamic in osteocytes and that BAIBA prevents their fission and breakdown. BAIBA is produced by contracted muscle, and whereas both old and young muscle produce BAIBA in response to contraction, old osteocytes from 22 month old mice are not protected by BAIBA to the same extent as young osteocytes from 5 month old mice. This suggests that it is not the levels of BAIBA that are defective with exercise with aging but that aged osteocytes can no longer respond to BAIBA. One receptor for BAIBA, known as the mas-related G-protein coupled receptor, type D, MRGPRD, was found to be most highly expressed in young osteocytes, but decreased in old osteocytes which may be why old osteocytes have reduced response to BAIBA. Our preliminary in vivo experiments where BAIBA is administered in drinking water to hindlimb unloaded 5 mo old mice suggests that BAIBA can retain not only bone mass but also muscle function. Our hypothesis is: Muscle in response to exercise produces factors such as BAIBA, that protect bone to maintain bone mass. This protection of bone by BAIBA is achieved by blocking or reducing the effects of reactive oxygen species, ROS, through the maintenance of osteocyte mitochondrial dynamics and their function. Exercise provides the positive effects of BAIBA on the skeleton with aging. To test this hypothesis, the specific aims of this project are: To determine the molecular mechanism used by BAIBA to protect and preserve bone viability and bone mass and to determine if BAIBA protects against bone loss and mediates some of the beneficial effects of exercise on bone and on muscle. Understanding how a low molecular molecule, ?-aminoisobutyric acid, produced by muscle, can block oxidative stress induced osteocyte cell death has the potential to lead to new therapeutics to prevent both bone and muscle loss with aging. As mitochondrial function in osteocytes is a new area of research, we may discover new means to prevent the effects of aging on bone by maintaining osteocyte viability and function.